1. Field of the Invention
The present disclosure provides a novel biphenyl compound or pharmaceutically acceptable salts thereof, methods for preparing the same, and pharmaceutical compositions for preventing or treating diabetic complications containing the same as an active ingredient.
2. Description of the Related Art
Diabetes mellitus is one of critical adult diseases all over the world. The prevalence rate of diabetes reaches 10% in Korea, and currently, the number of diabetes patients counts more than 240,000,000 over the world and is expected to reach 380,000,000 in 2025. It was reported by Journal of American Medical Association (JAMA) in 2009 that 60% of the expected total diabetes would occur in Asia.
Particularly, the time of onset of diabetes was moved forward young adults and middle-aged people. As life-time is extended, it is very hard to avoid developing complications. In other words, after 10-20 years from the onset of diabetes, almost every body organ is damaged to cause diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic heart diseases, diabetic cancers, diabetic osteoporosis, etc.
Chronic diabetic nephropathy becomes the most critical reason of hemodialysis treatment and end stage renal disease. Diabetic cataract and diabetic retinopathy cause sight loss and even lead to death. In USA, the major reason of sight loss in the age group of 25-74 is diabetes and 60% of diabetics lose their eye sight 15-20 years after the onset (Klein R., 1996, Annu. Rev. Public. Health. 66:366-78). In addition, diabetic retinopathy becomes the leading cause of blindness in adults, and the prevalence rate is rising (Sharkey T. P., 1971, J. Am. Diet. Ass. 58:528).
Therefore, only if the occurrence of complications is postponed 5-10 years, the quality of lives of diabetics and their families will be totally different, affecting significantly the national budget itself.
Representative factors that cause diabetic complications are as follows.
It was known that in a long-term hyperglycemic environment, advanced glycation endproducts (AGE) formed by nonenzymatic glycation of protein bind to proteins or lipids abnormally and irreversibly and activate receptors for advanced glycation endproducts (RAGE) abnormally, leading to develop diabetic complications.
Nonenzymatic glycation of protein indicates a condensation reaction of reducing sugars and amino acid groups such as lysine residue of protein, which is the Maillard reaction, without being mediated by an enzyme. As a result of this reaction, advanced glycation endproducts (AGE) are generated.
That is, nonenzymatic glycation of protein can be divided into two steps: (1) wherein amino acid groups such as lysine residue of protein react with aldehydes or ketones of reducing sugars without enzyme activity, which is a nucleophilic addition reaction, to produce the early stage product Schiff bases, and then ketoamine adducts residing close to the Schiff base react with each other by condensation to produce reversible Amadori type early glycation products; and (2) wherein when hyperglycemia status continues, the reversible Amadori type early glycation products are not degraded and rearranged to produce irreversible AGE, and the generated irreversible AGE are conjugated or cross-linked with proteins or lipids, leading to the generation of irreversible glycoprotein or glycolipids.
Unlike the reversible Amadori type early glycation products, AGE are irreversible reaction products and once generated, they are not degraded even when the blood glucose level is recovered to normal, and are accumulated in tissues as long as proteins or lipids to which AGE are conjugated survive, resulting in abnormal changes in structure and functions of tissues to cause complications all over tissues (Vinson, J. A. et al., 1996, J. Nutritional Biochemistry 7: 559-663; Smith, P. R. et al., 1992, Eur. J. Biochem., 210: 729-739).
For example, glycated albumin, one of AGE generated by the reaction between glucoses and many kinds of proteins, plays a critical role in causing chronic diabetic nephropathy. Glycated albumin can be introduced into glomerular cells more easily than normal albumin and high concentration of glucose stimulates mesangium cells to increase extracellular matrix synthesis. Due to excessively introduced glycated albumin and increased extracellular matrix, glomerular fibrosis is induced. By such a mechanism, glomerulus is continuously damaged, and at last, there is no choice but to use extreme therapeutic methods such as hemodialysis or organ transplantation.
In addition, it has been reported that due to chronic diabetes, collagens are conjugated with AGE in arterial wall and basement membrane proteins are conjugated with AGE in glomerulus, which are accumulated in tissues (Brownlee, M., et al., 1986, Sciences, 232, 1629-1632).
Such nonenzymatic glycation of protein induces glycosylation of basement membrane, proteins such as plasma albumin, lens protein, fibrin, collagen, etc. and AGE generated thereby causes abnormal changes in the structure and functions of tissues, leading to chronic diabetic complications such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, etc.
Like this, the mechanisms of nonenzymatic glycation are all connected to cause diabetic complications. Thus, it was revealed that it is very important to inhibit AGE formation in order to postpone, prevent or treat diabetic complications (Brownlee, M., et al., 1988, N. Engl. Med., 318, 1315-1321).
Currently, a protein glycosylation inhibitor and a synthetic medicine, aminoguanidine is a nucleophilic hydrazine and binds to Amadori products to prevent cross-linking with proteins, resulting in the inhibition of AGE formation, by which it can postpone or prevent the progress of diabetic complications (Brownlee, M., et al., 1986, Science, 232, 1629-1632; Edelstein, D. et al., 1992, Diabetes, 41, 26-29). Aminoguanidine is the most promising synthetic medicine for the prevention and treatment of diabetic complications, and the third phase clinical test has been completed. However, the clinical test of aminoguanidine has been stopped because of its toxicity observed during the long term administration. Accordingly, there is a need to develop a safer and more effective natural medicine.
For diabetic retinopathy, chronic retinal hypoxia, retinal ischemia, and an increased vascular permeability induce vitreous hemorrhage and eventually macular edema or angiogenesis, resulting in progress into proliferative diabetic retinopathy (Aiello L. P., Diabetes Care. 21:143-156). In this process, various causes are involved, and particularly, angiogenic growth factors which are known to be angiogenic factors and vascular permeability factors are seemed to play the most critical role. Angiogenic growth factors are expressed by early changes in diabetic retinopathy, and tight junction proteins such as occludin decrease, and eventually, the breakdown of blood-retinal barrier which is a physical barrier of retina increases blood permeability and aggravates retinopathy (Wang. W., 2001, Am. J. Physiol. Heart. Circ. Physiol. 280; H434-40).
There is still no drug of which effectiveness in preventing diabetic retinopathy or inhibiting the progression is proved. However, there is an attention being paid to development of an inhibiting agent against various growth factors, which are involved in angiogenesis, among many mechanisms for generating retinopathy.
Examples of current therapy for diabetic retinopathy include laser therapy and vitrectomy, etc. Most therapies are surgical and drug treatment is still being developed. The current drug treatment, intravitreal injection is often being carried out as a primary or additional treatment. Intravitreal injection causes direct and relatively rapid effects. The representative drug is angiogenesis inhibitors, and researches and therapeutic development on angiogenesis inhibitors are being actively conducted. Steroids inhibit the formation of vascular growth factors such as angiogenic growth factors which increase blood permeability, block the arachidonic acid pathway, and inhibit the formation of prostaglandins, and thus, are very effective for macular edema via anti-inflammatory function and blood-retinal barrier stabilization (Sutter F. K., 2004, Ophthalmology, 111: 2044-9). Recently, there have been reports that intravitreal injection of the anti-angiogenic growth factor (anti-VEGF) reduces macular edema caused by central retinal vein occlusion, and reduces blood permeability and fibrovascular proliferation in proliferative diabetic retinopathy (Avery R. L., 2006, Ophthalmology, 113:363-72; Spaide R. F., 2006, Retina, 26:275-8; Iturralde D., 2006, Retina, 26:279-84). However, Avastin is approved by the FDA as an anticancer agent, not for ocular uses. Like steroids, the effect would last only several months, and in some cases, the drug may cause cataract or glaucoma and require additional therapies. Accordingly, many researches have been proceeded to develop anti-angiogenic growth factors from foods or natural products which have no side effects.
Thus, the present inventors have performed researches to develop new therapeutic agents for diabetic complications derived from natural products, isolated a novel biphenyl compound from a medical herb Osteomeles schwerinae Schneid and identified that these compounds can be effectively used for the prevention or treatment of diabetic complications since these have inhibited AGE formation both in vitro and animal experiments (in vivo) and prevented significantly abnormal change in the tight junction protein occludin and VEGF, the early symptoms of diabetic retinopathy, thereby leading to completion of the present invention.